Publications

• NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

  Chen H., Li Y., Li H., Chen X., Fu H., Mao D., Chen W., Lan L., Wang C., Hu K., Li J., Zhu C., Evans I., Cheung E., Lu D., He Y., Behrens A., Yin D., Zhang C.

  The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically^1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells³. However, how ... >> More

  The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically^1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells³. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy. << Less

  Nature 631:663-669(2024) [PubMed] [EuropePMC]

• Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.

  Moreno-Yruela C., Zhang D., Wei W., Baek M., Liu W., Gao J., Dankova D., Nielsen A.L., Bolding J.E., Yang L., Jameson S.T., Wong J., Olsen C.A., Zhao Y.

  Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferas ... >> More

  Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε-<i>N</i>-L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements. << Less

  Sci. Adv. 8:eabi6696-eabi6696(2022) [PubMed] [EuropePMC]